HCMV infects many cell types in vivo and in vitro. While previous studies have identified several cellular proteins that may function at early steps of infection in a cell type dependent manner, the mechanism of virus entry is still poorly understood. This year, using a computational biology approach, correlating gene expression with virus infectivity in 54 cell lines, we identified THY-1 as a putative host determinant for HCMV infection in these cells. THY-1 is located on the cell surface of several cell types including fibroblasts, monocytes, and endothelial and epithelial cells which are all targets for HCMV infection. With a series of loss-of-function, gain-of-function and protein-protein interaction analyses, we found that THY-1 mediates HCMV infection at the entry step and is important for infection that occurs at a low inoculum of virus. THY-1 antibody that bound to the cell surface blocked HCMV during the initial 60 minutes of infection in a dose-dependent manner. Down-regulation of THY-1 expression using siRNA impaired infectivity that occurred during the initial 60 minutes of infection. Both THY-1 antibody and siRNA inhibited HCMV-induced activation of the PI3-K/Akt signaling pathway required for entry. Soluble THY-1 protein blocked HCMV infection during, but not after, virus internalization. Expression of exogenous THY-1 enhanced entry in cells expressing low levels of the protein. THY-1 interacted with HCMV glycoprotein B and glycoprotein H and may form a complex important for entry. However, since glycoprotein B and glycoprotein H have previously been shown to interact, it is uncertain if THY-1 directly binds to both of these proteins. Prior observations that THY-1 interacts with &#945;V&#946;3 integrin and recruits paxillin (implicated in HCMV entry), and that THYY-1 regulates leukocyte extravasation (critical for HCMV viremia) all support a role for THY-1 as an HCMV entry mediator in a cell type dependent manner. THY-1 may function through a complex setting, that would include viral glycoprotein B and glycoprotein H, and other cellular factors, thus links virus entry with signaling in host cells that ultimately leads to virus infection. Herpes simplex virus 2 (HSV-2) is the causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability are central to preventing and treating genital herpes. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because there have been only two genomes determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage clinical isolate strain, each from a different geographical area. This year, we reported the near-complete genome sequences of 34 HSV-2 low passage and laboratory strains, of which 14 were collected in Uganda, 1 in South Africa, 11 in the USA and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. The newly generated sequences more closely resemble the low passage SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV-2. This information will also contribute to our understanding of HSV evolution. HSV-1 and HSV-2 establish persistent infections in sensory neurons and commonly manifest with recurring oral or genital erosions that transmit virus. HSV encodes twelve predicted glycoproteins that serve various functions including cellular attachment, entry, and egress. Glycoprotein G is currently the target of an antibody test to differentiate HSV-1 from HSV-2; however, this test has shown reduced capacity to differentiate HSV strains in East Africa. Until the recent availability of 26 full-length HSV-1 and 36 full-length HSV-2 sequences, minimal comparative information was available for these viruses. This year we use a variety of sequence analysis methods to compare all available sequence data for HSV-1 and HSV-2 glycoproteins, using viruses isolated in Europe, Asia, North America, the Republic of South Africa and East Africa. We find numerous differences in diversity, amino acid substitution rates, and recombination rates between HSV-1 glycoproteins and their HSV-2 counterparts. Phylogenetic analysis revealed that while most global HSV-2 glycoprotein G sequences did not cluster within or between continents, one clade contained 37% of the African sequences analyzed. Accordingly, sequences from this African subset contained unique amino acid signatures, not only in glycoprotein G, but also in glycoproteins I and E, which may account for the failure of sensitive antibody tests to distinguish HSV-1 from HSV-2 in some African individuals. Overall, we found less glycoprotein sequence diversity within HSV-2 than within the HSV-1 strains studied, while at the same time, several HSV-2 glycoproteins were evolving under less selective pressure. Because HSV glycoproteins are the focus of antibody tests to detect and differentiate between infections with the two strains and are constituents of vaccines in clinical stage development, these findings will aid in refining the targets for diagnostic tests and vaccines.